Certain 7-(phenethylaminoalkyl)theophylline derivatives as lipolysis promoters

ABSTRACT

Certain 7-(phenethylaminoalkyl)theophylline derivatives promote lipolysis in swine.

DESCRIPTION OF THE INVENTION

It has been found that lipolysis in swine is promoted by certain7-(phenethylaminoalkyl)theophylline derivatives of the formula: ##STR1##wherein R is 1-piperidinyl, n is zero or one, both of R¹ and R² arehydrogen, or one is methyl or hydroxyl and the other is hydrogen, R³ ishydrogen or methyl, and Y is ##STR2## and their physiologicallyacceptable acid addition salts.

These compounds also can be named as β-phenyl-β-hydroxy(oroxo)ethylaminopropyl-3,7-dihydro-1,3-dimethyl-1H-purine-2,6-diones.

Suitable salts are those of such acids as acetic, succinic, maleic,fumaric, propionic, citric, lactic, hydrochloric, sulfuric andphosphoric acids.

Included in the invention are the individual optically active isomers,and diastereomers, as well as mixtures thereof, that promote lipolysis.

The compounds of Formula I are known: they, and methods for theirpreparation, are described in U.S. Pat. Nos. 3,728,346, 3,398,150,3,414,572 and 3,544,685, and Belgian Pat. No. 788,427.

The compounds of Formula I have been found to promote--i.e.,stimulate--lipolysis in swine tissue. The manner in which they causethis effect has not been established. Their effectiveness for thispurpose has been ascertained by the following procedure.

A mixture of (a) 150 milligrams of slices of pig adipose tissue,approximately 0.3 millimeter thick, (b) 3 milliliters of a Krebs-Ringerbicarbonate solution, pH=7.4, containing one-half the usual calcium ionconcentration, 4% fatty acid-free bovine serum albumin, 6.6 milligramsof L-ascorbic acid per milliliter, 2 milligrams of glucose permilliliter, and (c) sufficient of a solution or suspension of the testcompound in dimethyl sulfoxide (DMSO), so that the final DMSOconcentration in the mixture was 5%, and the test compound was presentat a concentration of one microgram per milliliter of the mixture wasincubated for 90 minutes at 37° C. Two replicates, taken from the tissueof one pig, were tested. The rate of lipolysis was determined bytitration of the fatty acids that had been released to the medium: thetissue was removed by filtration through cheesecloth; to 0.5 milliliterof the filtrate was added 0.5 milliliter of 0.9% sodium chloridesolution and 5 milliliters of a solution consisting of (by volume) 40parts of isopropanol, 10 parts of heptane and 1 part of 1 N sulfuricacid. The mixture was allowed to stand for 5 minutes at roomtemperature. Then 3 milliliters of heptane and 2 milliliters of waterwere added. The mixture was shaken for 10 minutes, then was held untilthe liquid phases separated. Duplicate 1.5 milliliter aliquots of theupper phase were titrated with tetra N-butyl ammonium hydroxide, using0.5 milliliter of methanolic Phenol Red as indicator. The basal rate oflipolysis (no test compound present) was subtracted. Test compoundactivity was expressed as the percent of maximal activity, estimated foreach test as the activity in the presence of 16 micromolar epinephrine(L-epinephrine bitartrate). Each test compound was independentlyevaluated twice using tissue from two different pigs, and the percent ofmaximal activity indicated is the average of the two experiments.

The hydrochloride salts of the following individual species of thecompounds of Formula I were tested. (For simplification, the species arecharacterized in terms of Formula I.):

    ______________________________________                                        Test Compound                                                                 No.         n      R.sup.1  R.sup.2                                                                            R.sup.3                                                                              Y                                     ______________________________________                                        1           0      CH.sub.3 H    H                                                                                     ##STR3##                             2           "      H        "    CH.sub.3                                                                             "                                     3           1      "        "    H      "                                      4.sup.a    0      "        "    "      "                                     5           "      "        "    "                                                                                     ##STR4##                             6           "      OH       "    "                                                                                     ##STR5##                              7.sup.a    "      H        "    "      "                                     ______________________________________                                         .sup.a Compound 7 is the racemic mixture; compound 4 is the corresponding     (+) optical isomer.                                                      

The results are reported in the following table.

    ______________________________________                                        Compound            Percent                                                   No.                 Stimulation                                               ______________________________________                                        1                   95                                                        2                   97                                                        3                   94                                                        4                   101                                                       5                   95                                                        6                   102                                                       7                   104                                                       ______________________________________                                    

The compounds of Formula I can be used to promote lipolysis in swine byadministering an effective amount of one or a mixture of two or more ofthe compounds orally or parenterally to the animal. They may beadministered as such, or as an active ingredient of a conventionalpharmaceutical formulation. They may be administered orally by anyconvenient means. Thus, they may be orally administered as a drench, byintubation, in the animal's food and water, in a food supplement or in aformulation expressly designed for administration of the drug. Suitableformulations include solutions, suspensions, dispersions, emulsions,tablets, boluses, powders, granules, capsules, syrups and elixirs. Forparenteral administration, they may be in the form of a solution,suspension, dispersion or emulsion. They can be administered in the formof an implant or other controlled sustained release formulation. Inertcarriers, such as one or more of water , edible oil, gelatin, lactose,starch, magnesium stearate, talc or vegetable gum can be used. Thedosage of the compound needed to promote lipolysis will depend upon theparticular compound used, and the particular animal being treated.However, in general, satisfactory results are obtained when thecompounds are administered in a dosage of from about 1 to about 500milligrams per kilogram of the animal's body weight. The compound can beadministered in a single dose or in a series of doses in the same day,or over a period of days. For any particular animal, a specific dosageregimen should be adjusted according to the individual need, theparticular compound(s) used as the promoters and the professionaljudgment of the person administering or supervising the administrationof the promoter. It is to be understood that the dosages set forthherein are exemplary only, and that they do not, to any extent, limitthe scope or practice of the invention.

I claim:
 1. A method of promoting lipolysis in swine which comprisesadministering, to a pig in need of such treatment, orally orparenterally, an effective dosage of a compound of the formula: ##STR6##wherein R is 1-piperidinyl, n is zero or one, both of R¹ and R² arehydrogen, or one is methyl or hydroxyl and the other is hydrogen, R³ ishydrogen or methyl, and Y is ##STR7## and their physiologicallyacceptable acid addition salts.